Reference Detail

Ref Type

Journal Article

PMID

(30819666)

Authors

Hayes TK, Luo F, Cohen O, Goodale AB, Lee Y, Pantel S, Bagul M, Piccioni F, Root DE, Garraway LA, Meyerson M, Johannessen CM

Title

A Functional Landscape of Resistance to MEK1/2 and CDK4/6 Inhibition in NRAS-Mutant Melanoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	79	9	2019 May 01	2352-2366	Cancer Res

URL

Abstract Text

Combinatorial inhibition of MEK1/2 and CDK4/6 is currently undergoing clinical investigation in NRAS-mutant melanoma. To prospectively map the landscape of resistance to this investigational regimen, we utilized a series of gain- and loss-of-function forward genetic screens to identify modulators of resistance to clinical inhibitors of MEK1/2 and CDK4/6 alone and in combination. First, we identified NRAS-mutant melanoma cell lines that were dependent on NRAS for proliferation and sensitive to MEK1/2 and CDK4/6 combination treatment. We then used a genome-scale ORF overexpression screen and a CRISPR knockout screen to identify modulators of resistance to each inhibitor alone or in combination. These orthogonal screening approaches revealed concordant means of achieving resistance to this therapeutic modality, including tyrosine kinases, RAF, RAS, AKT, and PI3K signaling. Activated KRAS was sufficient to cause resistance to combined MEK/CDK inhibition and to replace genetic depletion of oncogenic NRAS. In summary, our comprehensive functional genetic screening approach revealed modulation of resistance to the inhibition of MEK1/2, CDK4/6, or their combination in NRAS-mutant melanoma. SIGNIFICANCE: These findings reveal that NRAS-mutant melanomas can acquire resistance to genetic ablation of NRAS or combination MEK1/2 and CDK4/6 inhibition by upregulating activity of the RTK-RAS-RAF and RTK-PI3K-AKT signaling cascade.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS mutant	melanoma	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, NRAS-mutant melanoma cell lines were sensitive to treatment with Mekinist (trametinib) in culture, demonstrating decreased cell viability, colony formation, and pathway activity, and increased cell cycle arrest (PMID: 30819666).	30819666
NRAS Q61L NRAS mut	melanoma	decreased response	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, NRAS-mutant melanoma cells expressing NRAS Q61L demonstrated a decreased response to treatment with Ibrance (palbociclib) in culture when compared to control (PMID: 30819666).	30819666
NRAS mut PIK3CA H1047R	melanoma	predicted - resistant	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, one of two NRAS-mutant melanoma cell lines expressing PIK3CA H1047R demonstrated resistance to treatment with Mekinist (trametinib) in culture (PMID: 30819666).	30819666
NRAS mutant	melanoma	conflicting	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, NRAS-mutant melanoma cell lines were sensitive to treatment with Ibrance (palbociclib) in culture, demonstrating decreased cell viability, colony formation, and pathway activity, and increased cell cycle arrest (PMID: 30819666).	30819666
NRAS Q61L NRAS mut	melanoma	predicted - resistant	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, NRAS-mutant melanoma cells expressing NRAS Q61L demonstrated resistance to treatment with Mekinist (trametinib) in culture (PMID: 30819666).	30819666
NRAS Q61L NRAS mut	melanoma	predicted - resistant	Palbociclib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, NRAS-mutant melanoma cells expressing NRAS Q61L demonstrated resistance to the combination treatment with Mekinist (trametinib) and Ibrance (palbociclib) in culture (PMID: 30819666).	30819666
NRAS mut PIK3CA E545K	melanoma	predicted - resistant	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, two of two NRAS-mutant melanoma cell lines expressing PIK3CA E545K demonstrated resistance to treatment with Ibrance (palbociclib) in culture (PMID: 30819666).	30819666
NRAS mut PIK3CA E545K	melanoma	predicted - resistant	Palbociclib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, four of four NRAS-mutant melanoma cell lines expressing PIK3CA E545K were resistant to the combination treatment of Ibrance (palbociclib) and Mekinist (trametinib) in culture (PMID: 30819666).	30819666
NRAS Q61K NRAS mut	melanoma	predicted - resistant	Palbociclib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, NRAS-mutant melanoma cells expressing NRAS Q61K demonstrated resistance to the combination treatment of Mekinist (trametinib) and Ibrance (palbociclib) in culture (PMID: 30819666).	30819666
NRAS mut PIK3CA E545K	melanoma	predicted - resistant	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, NRAS-mutant melanoma cell lines expressing PIK3CA E545K demonstrated resistance to treatment with Mekinist (trametinib) in culture (PMID: 30819666).	30819666
NRAS Q61K NRAS mut	melanoma	predicted - resistant	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, NRAS-mutant melanoma cells expressing NRAS Q61K demonstrated resistance to treatment with Mekinist (trametinib) in culture (PMID: 30819666).	30819666
NRAS Q61K NRAS mut	melanoma	decreased response	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, NRAS-mutant melanoma cells expressing NRAS Q61K demonstrated a decreased response to treatment with Ibrance (palbociclib) in culture compared to control (PMID: 30819666).	30819666
NRAS mutant	melanoma	predicted - sensitive	Palbociclib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cell lines harboring an NRAS mutation were sensitive to the combination therapy of Ibrance (palbociclib) and Mekinist (trametinib) in culture, demonstrating reduced cell viability, colony formation, and pathway activity, and increased cell cycle arrest (PMID: 30819666).	30819666